Androgen dependence of spermatogenesis

5.4.1 Neonatal androgen secretion

A distinct peak of testosterone synthesis and secretion occurs perinatally and -depending on the species - is of variable duration during the neonatal period. The physiological significance of this activation of testosterone production is not entirely clear. In the rat model, blockade of the neonatal androgen secretion by a GnRH antagonist provoked a delay of puberty and infertility in the adult animals (Kolho and Huhtaniemi 1989a; 1989b). Surprisingly, spermatogenesis remained unaffected and infertility resulted from the inability to inseminate the females during mating. However, the infertile status progressively reverted over time and following an observation period of 350 days, animals regained fertility.

Long-term studies were also conducted in two nonhuman primate models, the rhesus monkey and the common marmoset. In these studies, neonatal androgen secretion was either blocked by the administration of GnRH agonist or antagonist. This interference delayed pubertal onset and attenuated the testicular weight gain (Mann etal. 1993; 1998; McKinnell etal. 2001; Sharpe etal. 2000). Penile length and detachment of prepuce were also affected transiently but recovered by week 52 (Brown et al. 1999). Animals were followed until adulthood and various male reproductive parameters including fertility and mating behaviour (Lunn etal. 1994) were assessed. No untoward effects on testicular function and fertility could be detected (Lunn et al. 1997). Hence, on the basis of available data, it appears that the neonatal testosterone peak is not related to subsequent development of male reproductive functions, timing of puberty and fertility. The only effect of loss of neonatal testosterone production that could be unravelled in adulthood was a dysfunction of some specific aspects of the immune system (Mann and Fraser 1996).

5.4.2 Pubertal initiation of spermatogenesis

Induction of spermatogenesis can be achieved in immature nonhuman primates by the administration of very high doses of testosterone although the number of spermatozoa in the ejaculate remained rather low (Marshall et al. 1984). This finding is in agreement with the earlier clinical observations that in boys with Leydig cell tumors, spermatogenesis was observed in those testicular areas bearing the tumor cells and producing high amounts of testosterone (Weinbauer and Nieschlag 1996, for details). These data would indeed suggest a direct local effect of testosterone.

Physiological

Experimentally-induced hormone deficiency or

situation

pathophysiological situation (hypogonadotroplc hypogonadism)

Normalcy

Initiation

Maintenance

Reinitiation

Suppression

T + FSH

T FSH T + FSH

T FSH T + FSH

T FSH T+FSH

T FSH T+FSH

1 1

1 1 1

1 1 1

11 1

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o

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o o O

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1 Normozoospermla ( ' Oliqozoospermia O Azoospermia

1 Normozoospermla ( ' Oliqozoospermia O Azoospermia

Fig. 5.3 Schematic representation of the role of follicle-stimulating hormone (FSH) and testosterone (T) alone or in combination for spermatogenesis in the primate. For normozoospermia (quantitatively normal spermatogenesis) both hormones are necessary and, conversely, the complete inhibition of spermatogenesis (azoospermia) requires suppression of both hormones. In clinical practice, both hormones are needed to re-establish fertility. In mice transgenic for human FSH or human FSH receptor, FSH action is not sufficient to induce the complete spermatogenic process. Because of the prolonged period of prepubertal quiescence in the primate, it is not clear whether FSH alone can initiate spermatogenesis. In the hpg mouse estradiol stimulates the complete spermatogenic process but this may involve concomitant FSH release and may not be applicable to primates.

More recently, analysis of testicular development in boys with activating mutations of the LH receptor has confirmed the concept that testosterone can initiate precocious puberty and maturation of the male gonad (Gromoll et al. 1998; Shenker etal. 1993).

Meanwhile it has become well established that testosterone is in fact essential to enable timely initiation of puberty. This knowledge stems from patients with inactivating mutations of the LH receptor. Aside from other effects such as reduced height and retarded bone maturation, these patients have comparatively small testes suggesting an impairment of germ cell development in association with reduced/absent local testicular testosterone production (Gromoll etal. 2000; Kremer etal. 1995).

Although these data clearly demonstrate the ability of testosterone to initiate the spermatogenic process (Fig. 5.3), they do not prove that testosterone is indispensable for the commencement of this process. "Fertile eunuchs" have atrophied Leydig cells but complete spermatogenesis (Behre et al. 2000). A patient with normal to slightly elevated gonadotropin levels along with a markedly reduced testosterone concentration but complete spermatogenesis has been described (de Roux et al. 1997). Hence it appears quite possible that spermatogenic induction can occur at least in the presence of substantially lowered testosterone levels.

Whereas there has been some debate previously as to whether testosterone can initiate the complete spermatogenic process in rats and mice, this issue is now better understood. In the hypogonadal (hpg) mouse lacking endogenous gonadotropin secretion, testosterone induced sperm formation and these sperm were fertile in vitro (Singh et al. 1995). In the rat the evidence is more indirect but also suggestive of a role for testosterone. Immunization of 18-day old rats against the LH receptor caused a 50% reduction of testicular sperm counts by 88 days of age (Graf etal. 1997).

Estradiol, in the adult male, directly interferes with gonadotropin production and secretion through negative feedback action followed by complete testicular involution and cessation of spermatogenesis. However, in the immature rat and mouse, treatment with estradiol provoked an increase of germ cell numbers (Ebling et al. 2000; Kula 1988). The study by Ebling etal. was conducted in hpg-mice and qualitatively normal spermatogenesis was induced by estradiol within 70 days. Since estradiol treatment also elevated FSH levels, it is possible, however, that the observed testicular effects of estradiol were indirect and at least partly mediated via FSH (Fig. 5.3).

It must be pointed out that during pubertal initiation, testosterone also stimulates growth hormone secretion and growth hormone-dependent growth factor levels. Whereas no evidence points to a role of GH in adult spermatogenesis (Sjogren et al. 1999), this is less clear for the developing testis. In GH-deficient and IGF-I/II-deficient animal models, testes - and body and organ size in general - are smaller. However, spermatogenesis is complete in these small testes, suggesting no direct involvement of GH and growth factors in initiation of spermatogenesis. For the GH-deficient dwarf rat it has been reported that spermatogenesis is also quantitatively normal (Bartlett etal. 1990b).

5.4.3 Adult spermatogenesis: maintenance and reinitiation

Much experimental work has been conducted in several animal species including nonhuman primates in order to clarify whether testosterone alone can maintain spermatogenesis. Suppression of LH/FSH secretion followed by concurrent and selective LH/testosterone replacement demonstrated unequivocally that testosterone alone could maintain qualitatively normal spermatogenesis, at least for the observation periods chosen. Studies employing selective immunization against LH or the LH receptor provided further support for a role of testosterone even in the presence of continued FSH secretion (Graf etal. 1997; Suresh etal. 1995). In a particular experimental setting, i.e. rats actively immunized against GnRH or depleted of Leydig cells, and supplemented with testosterone, even quantitatively normal spermatogenesis was maintained (Awoniyi etal. 1992; Sharpe etal. 1988a; 1988b).

In most instances, the experimental paradigm for animal studies differs largely from the clinical situation. While high doses of exogenous testosterone are used in animal experimentation, hCG is used for clinical therapy. The sustained use of hCG in animals, however, is obviated by the antigenic response to hCG and the development of neutralizing antibodies. Hence, in animals, high doses of testosterone must be given in order to achieve sufficient testicular androgen concentrations, whereas in patients Leydig cells and testosterone production are stimulated directly.

The clinical evidence derived from hypogonadotropic hypogonadal patients under endocrine therapy demonstrated that testosterone can maintain spermatogenesis but only to a qualitative extent. It must also be recognized that the successful reinitiation of spermatogenesis requires the addition of FSH activity (either via pulsatile GnRH or administration of hMG or urinary/recombinant human FSH) in most instances. In these studies, hCG is administered to patients, thus providing direct stimulation of Leydig cells and endogenous testosterone production (McLachlan 2000; Nieschlag etal. 1999). If patients continue only on testosterone substitution via hCG yielding normal peripheral androgen levels, the stimulatory effect on spermatogenesis is only maintained in a qualitative manner and sperm numbers decline over time (Depenbusch etal. 2002). This study and others (Meriggiola et al. 2002) confirm and extend earlier reports (Johnsen 1978; Vicari et al. 1992) and clearly show that testosterone alone can maintain spermatogenesis but only to a qualitatively normal extent. Vicari et al. (1992) also reported complete reinitiation of spermatogenesis by hCG alone in hypogonadotropic hypogonadal patients.

Thus, maintenance and reinitiation of spermatogenesis by testosterone/hCG in patients are possible (Nieschlag etal. 1999; Fig. 5.3). The certain diversity of results may result from the fact that hypogonadotropic hypogonadism is not a monocausal diseasebut may stem from various deficiencies (idiopathic hypogonadotropic hypo-gonadism, pre- and post-pubertal pituitary insufficiency, Kallmann syndrome). Also the preceding history of therapy and pretherapy testicular volume contribute to differential responsiveness of the patients (Liu et al. 2002). Comparing doses, reinitiation of spermatogenesis seems to require more testosterone - either higher doses or longer duration of exposure - than maintenance of spermatogenesis. This became particularly evident from studies using GnRH analogues and testosterone substation: concomitant supplementation with testosterone prevented the induction of azoospermia, whereas delayed substitution with the same dose of testosterone failed to do so (Weinbauer and Nieschlag 1996).

If very high doses of testosterone are used it is possible to restore spermatogenesis to a qualitatively normal extent in experimental models including the nonhuman primate. It was also shown in the Leydig cell-depleted rat model and the GnRH-immunized rat model, that high amounts of testosterone almost quantitatively maintained or restored normal spermatogenesis (Awoniyi et al. 1992; Sharpe et al. 1988a; 1988b). It must be noted, however, that androgen receptors are present in many organs (Dankbar etal. 1995) and that the animals were exposed to exorbitantly high androgen levels in some of these studies. Hence the possibility cannot be ruled out entirely that the observed effects on spermatogenesis not only represent a selective and specific effect of testosterone on the testis but also a systemic action under pharmacological conditions.

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